This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this study is to evaluate the safety and therapeutic potential of in vivo blockade of interactions between the inhibitory receptor PD-1 and its ligands using SIV/macaque model. Our hypothesis is that blockade of interactions between PD-1 and its ligands can provide therapeutic benefit by eliciting cell mediated immunity capable of providing better viral control than the functionality limited T cells characteristic of chronic SIV infections. Here we performed the PD-1 blockade during chronic SIV infections and our results demonstrate that PD-1 blockade using an antibody to PD-1 is well tolerated and results in rapid expansion of virus-specific CD8 T cells with improved functional quality. This enhanced T-cell immunity was seen in the blood and also in the gut, a major reservoir of SIV infection. Interestingly, PD-1 blockade also resulted in proliferation of memory B cells and increases in SIV envelope-specific antibody. These improved immune responses were associated with significant reductions in plasma viral load and also prolonged the survival of SIV-infected macaques. Blockade was effective during the early (week 10) as well as late (~week 90) phases of chronic infection even under conditions of severe lymphopenia. These results demonstrate enhancement of both cellular and humoral immune responses during a pathogenic immunodeficiency virus infection by blocking a single inhibitory pathway and identify a novel therapeutic approach for human immunodeficiency virus/acquired immunodeficiency syndrome (Velu et al., 2008). Currently, we are evaluating the therapeutic potential of blockade of PD-1: PD-1 ligand pathway in combination with anti-retroviral therapy in SIV infected macaques and evaluating the immune restoration potential of PD-1 ligands using SIV macaque model.